Mechanisms and Consequences of Intermittent Hypoxia-Induced Lipolysis Candidate: Dr. Jonathan Jun recently completed a 5-year fellowship at Johns Hopkins in Pulmonary, Critical Care, and Sleep Medicine. He has been working in the laboratory of Dr. Vsevolod Polotsky, a pioneer in the use of intermittent hypoxia (IH) in mice to study metabolic consequences of obstructive sleep apnea (OSA). In this proposal, Dr. Jun tests a novel theory to explain the metabolic dysfunction induced by IH. Environment: Dr. Jun is an Instructor in the Division of Pulmonary/Critical Care Medicine beginning on July 1, 2011 to pursue a clinician-scientist career. He will receive ongoing training and support through Dr. Polotsky and a panel of experts in physiology and metabolism at Johns Hopkins and the University of Maryland. Research: OSA is a common condition characterized by repetitive upper airway collapse, causing IH and sleep fragmentation. OSA may predispose to metabolic dysfunction and atherosclerotic cardiovascular disease, thereby contributing to the leading causes of death and disability in the Western world. Several investigators have demonstrated that experimental IH causes insulin resistance and hyperlipidemia. However the basis for these IH-induced metabolic abnormalities is not understood. We hypothesize that elevations of free fatty acids (FFA) may cause metabolic dysfunction during IH. FFA are circulating lipids released by adipose tissue during lipolysis, which in excess induce insulin resistance, fatty liver, and hyperlipidemia. We recently reported that OSA rapidly increases plasma FFA during sleep, which is abolished by supplemental oxygen. This observation inspired the hypotheses central to this proposal, that (1) lipolysis during IH occurs through carotid body stimulation of the sympathetic nervous system, and that (2) chronic IH-induced lipolysis promotes tissue lipid accumulations leading to insulin resistance and dyslipidemia. A mouse model of IH, simulating oxygen desaturations experienced by patients with OSA, has been developed to test these hypotheses. Mice exhibit rapid increases in FFA and glycerol levels during IH. In Specific Aim 1, we will establish the role of the carotid body in stimulating lipolysis during IH, using mice lackig normal carotid body function. Specific Aim 2 will establish the role of the sympathetic nervous system in stimulating lipolysis during IH, using beta blockade. Specific Aim 3 will establish whether insulin resistance and hyperlipidemia following chronic IH can be prevented with the suppression of lipolysis. Public Health Relevance: Successful completion of these aims will establish the central role of lipolysis in the metabolic consequences of IH and OSA. Potentially, devastating cardiovascular consequences of OSA may be averted by recognizing and preventing IH-induced lipolysis. PUBLIC HEALTH RELEVANCE: Obstructive sleep apnea causes intermittent hypoxia during sleep, and affects as many as 24% of men 9% of women in the United States. Obstructive sleep apnea is associated with insulin resistance and hyperlipidemia which are major risk factors for atherosclerosis, the nation's leading cause of death. Research proposed in this grant submission will determine how the intermittent hypoxia of sleep apnea causes insulin resistance and hyperlipidemia.